Elucidation of the physiological function of ALS2 and mechanism for motor neuron degeneration through the identification of ALS2 activators

肌萎缩性侧索硬化症（ALS）是一种异质性进行性神经退行性疾病，其特征是大脑皮层、脑干和脊髓中运动神经元的选择性丧失。目前，运动神经元选择性变性的机制尚不清楚。我们将重点关注新发现的ALS致病基因产物ALS2，并研究ALS2及其激活因子的分子功能。我们在此鉴定了Rac1作为一种新的ALS2激活因子，并揭示了ALS2在细胞巨噬细胞和核内体融合中发挥作用。我们的研究将有助于明确肌萎缩侧索硬化症神经元功能障碍和退行性变的分子机制。

Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of progressive neurodegenerative disorders characterized by a selective loss of motor neurons in the cerebral cortex, brainstem, and spinal cord. Currently, the mechanism for the selective degeneration of motor neurons is unclear. We focus on the newly-identified ALS causative gene product, called ALS2, and investigate the molecular function of ALS2 and its activators. We here identified Rac1 as a novel ALS2 activator, and revealed that ALS2 plays a role in macropinocytosis and endosome fusion in cells. Our study will contribute to,define the molecular mechanisms underlying the neuronal dysfunction and degeneration in ALS.